DOI 10.1007/s00296-013-2901-2 ORIGINAL ARTICLE Unexpected association between joint hypermobility syndrome/ehlers Danlos syndrome hypermobility type and obsessive compulsive personality disorder Massimo Pasquini Claudia Celletti Isabella Berardelli Valentina Roselli Simona Mastroeni Marco Castori Massimo Biondi Filippo Camerota Received: 22 September 2012 / Accepted: 6 November 2013 Springer-Verlag Berlin Heidelberg 2013 Abstract Joint hypermobility syndrome/ehlers Danlos syndrome hypermobility type (JHS/EDS-HT) is a largely unrecognized, heritable connective tissue disorder, mainly characterized by joint instability complications, widespread musculoskeletal pain, and minor skin features. In a case control study, 47 consecutive JHS/EDS-HT patients were investigated for the prevalence of psychiatric disorders and compared to 45 healthy controls in a single center. The psychiatric evaluation consisted of structured clinical interview for DSM-IV criteria by using the SCID-I and the SCID-II. Symptom severity was assessed using the Hamilton Anxiety Rating Scale (HAM-A), the Hamilton Depression Rating Scale (HAM-D), and the Brief Psychiatric Rating Scale (BPRS). The Global Assessment of Functioning Scale (GAF) was used to assess the overall severity of psychological, social, and occupational functions. JHS/EDS-HT patients had significantly higher mean scores for all questionnaires: HAM-A (6.7 vs. 3.8), HAM-D (6.4 vs. 2.7), GAF (75.0 vs. 86.1), and BPRS (27.5 vs. 25.6). M. Pasquini I. Berardelli V. Roselli M. Biondi Department of Neurology and Psychiatry, Umberto I Hospital, Sapienza University of Rome, Rome, Italy C. Celletti (*) F. Camerota Physical Medicine and Rehabilitation Division, Umberto I Hospital, Sapienza University of Rome, Rome, Italy e-mail: c_celletti@libero.it S. Mastroeni Clinical Epidemiology Unit, IDI-IRCSS, Rome, Italy M. Castori Division of Medical Genetics, Department of Molecular Medicine, San Camillo-Forlanini Hospital, Sapienza University of Rome, Rome, Italy The JHS/EDS-HT group had a 4.3 higher risk of being affected by any psychiatric disorder, and in particular, a 5.8 higher risk of having a personality disorder. In particular, 5 JHS/EDS-HT suffered from obsessive compulsive personality disorder with an observed prevalence rate of 10.6 % (3.6 23.1). Psychiatric assessment of JHS/EDS-HT patients showed an extremely high prevalence of personality disorders (21 %), and of Axis-I disorders (38 %), mostly depressive. This study did not confirm the previously reported increased rate of panic disorders in JHS/EDS-HT. Keywords Anxiety disorder Connective tissue disorder Depressive disorder Ehlers Danlos syndrome Joint hypermobility Obsessive compulsive personality disorder Personality disorder Introduction Joint hypermobility syndrome (JHS) is a common, but still largely unrecognized, heritable connective tissue disorder, mainly characterized by joint hypermobility (JHM), joint instability, widespread chronic pain, and minor skin features [1]. JHS is now considered one and the same with the Ehlers Danlos syndrome hypermobility type (EDS-HT) [2] and two clinically undistinguishable disorders. Although still considered a rare condition, the JHS/EDS-HT complex may have a presumed population prevalence ranging from 0.75 to 2 % [3]. JHS/EDS-HT is an exclusion diagnosis based on specific diagnostic criteria [4, 5], but patients assessment is still hampered by the lack of a confirmatory laboratory test [6]. Historically, the musculoskeletal system is the mostly affected body compartment with an exceptionally high rate of joint complications, such as arthralgias, sprains, strains, subluxations, and dislocations, as well
as myalgias and fatigue, all symptoms which preluding the development of a chronic widespread musculoskeletal pain syndrome [1, 7]. More recent research points out the existence of a wide variety of extra-articular features, extending but not limited to the cardiovascular, ocular, visceral, and central nervous system [8]. Practice suggests a major role for behavior and psychological health in the development and/or perpetuations of some chronic disabilities in JHS/EDS-HT [9]. In 1994, by studying 48 Ehlers Danlos syndrome patients (including eleven with EDS-HT and five with JHS), Lumley et al. [10] detected a high rate of anxiety, depression, anger, and interpersonal concerns. Subsequent studies report a considerable excess of emotional symptoms [11] and psychological distress, and somatosensory amplification [12] in JHS/EDS-HT patients. JHS/EDS resulted more common among patients suffering from anxiety and panic disorders, and in turn, these complaints are frequently reported in JHS/EDS-HT [13, 14]. In particular, JHS was diagnosed in 67.7 % of patients with anxiety disorder, while it was demonstrated in 10.1 and 12.5 % of psychiatric patients and controls [15]. In a non-clinical population of 526 subjects, a significant difference for trait anxiety but not for state anxiety was reported [16]. Finally, in a 15-year-follow-up study, Bulbena et al. [17] estimated an absolute risk for panic disorders of 44.1 % among JHS cases compared to 2.8 % for non-jhs subjects. The mechanisms underlying such an association remain obscure. The high rate of medically unexplained symptoms and chronic pain may be a major contributor [8, 9] but it likely does not explain the entire range of behavior/psychiatric features observed in JHS/EDS-HT. Within this gap of knowledge, no data regarding personality disorders and JHS/EDS-HT exist. To further investigate the association between psychiatric disorders and JHS/EDS-HT, we conducted a single-center, case control study comparing 47 JHS/EDS-HT patients with 45 matched controls with a set of psychiatric tools. Methods Forty-seven consecutive patients with JHS/EDS-HT who attended the outpatient clinic at the Physical and Rehabilitation Division, Sapienza University of Rome, between September 2010 and October 2011 were recruited as cases. Controls were 45 healthy subjects of similar age, sex, education, geographical, and social origin recruited from medical students, hospital staff members, and residents in the same period at the Department of Neurology and Psychiatry. All patients agreed to participate in this study. Diagnosis of JHS/EDS-HT was based on published diagnostic criteria including the Brighton criteria for JHS [5] and the Villefranche criteria for EDS-HT [4] (Table 1). Patients were included if they met at least one of these two criteria sets. In our clinical practice, the Brighton criteria are the most stringent for young-adult, adult, and elder patients, while the Villefranche criteria are best for individuals of paediatric age. For this study, JHS was mainly assessed applying the Beighton score. Beighton score is a nine-point evaluation with the attribution of one point in the presence of any of the following: (a) passive apposition of the thumb to the flexor aspect of the forearm (one point for each hand), (b) passive dorsiflexion of the V finger beyond 90 (one point for each hand), (c) hyperextension of the elbow beyond 10 (one point for each harm), (d) hyperextension of the knee Table 1 Applied diagnostic criteria in our patients sample Brighton criteria (JHS) Major criteria Villefranche criteria (EDS-HT) Major criteria Beighton score 4/9 Beighton score 5/9 Arthralgia for > 3 months in > 4 joints Skin involvement (hyperextensibility and/or smooth, velvety skin) Minor criteria Minor criteria Beighton score of 1 3 Recurring joint dislocations Arthralgia in 1 3 joints Chronic joint/limb pain History of joint dislocations Positive family history Soft tissue lesions > 3 Marfan-like habitus Skin striae, hyperextensibility, or scarring Eye signs, lid laxity History of varicose veins, hernia, visceral prolapse For the diagnosis: both major, or 1 major and 2 minor, or 4 minor criteria and the exclusion of other heritable connective tissue disorders For the diagnosis: both major features; the presence of one or more minor features was useful for the differential from partially overlapping heritable connective tissue disorders
beyond 10 (one point for each leg), and (e) forward flexion of the trunk with the knee extended and the palm resting flat on the floor. The study was approved by the local ethical committee, and all patients gave their informed consent before participating. Exclusion criteria were severe neurological or clinically significant medical disorders. Clinical and demographic information collected at interview included age, sex, JHS/EDS-HT duration, and medications for other disorders. The psychiatric evaluation was performed by two trained psychiatrists and was based on the structured clinical interview for DSM-IV criteria using the structured clinical interview (SCID-I) for Axis-I disorders [18] and the SCID-II for Axis-II disorders [19]. The Hamilton Anxiety Rating Scale (HAM-A) [20] was administered to evaluate the severity of anxiety symptoms; the Hamilton Depression Rating Scale (HAM-D) [21] was used to assess the severity of depressive symptoms; the Brief Psychiatric Rating Scale (BPRS) [22] was administered to evaluate the presence of psychotic symptoms. The Global Assessment of Functioning Scale (GAF) [18] was used to assess the overall severity of psychological, social, and occupational functions not related to the presence and severity of EDS-HT. To estimate odds ratios (OR) and 95 % confidence intervals (95 % CI), all these variables were dichotomized as the presence/absence of symptoms or high/low or positive/negative as specified: HAM-A presence 13; HAM-D presence 8; GAF presence 70; BPRS high 25 that corresponds to the upper tercile of controls; SCID-I and SCID-II positive: the presence of at least one symptom. Data are presented as proportions, mean ± SD, and medians. Two-sample comparisons of proportions were performed by Fisher s exact test; for normally distributed variables, by Student s t test; and for non-normally distributed variables, by the Mann Whitney U test. Skewness and kurtosis test were used to assess normality. Considering the low category as the referent, ORs and 95 % CI for the higher category were estimated to asses the likelihood to present the joint hypermobility syndrome. Haldane correction was used where appropriate. Statistical significance was set at P < 0.05. The computer package Stata 11 (Stata Corp. LP, College Station, TX, USA) [23] was employed for the statistical analyses. Results The mean age of the 92 subjects was 31 years (SD = 13) and 81.5 % were women. The two samples did not differ by sex, age, and years of education (Table 2). JHS/EDS-HT patients collected significantly higher mean scores for all questionnaires HAM-A (6.7 vs. 3.8), HAM-D (6.4 vs. 2.7), GAF (75.0 vs. 86.1), and BPRS (27.5 vs. 25.6) (Mann Whitney U test, P < 0.01). This association remained Table 2 Demographic and clinical characteristics of cases and controls Characteristics Cases (N = 47) Controls (N = 45) P value a Sex no. (%) Females 41 (87.2) 34 (75.6) Males 6 (12.8) 11 (24.4) 0.18 b Age (years) Mean 32.4 29.8 SD 12.7 13.1 0.28 Education no. (%) HAM-A HAM-A Hamilton Anxiety Rating Scale, HAM-D Hamilton Depression Rating Scale, GAF Global Assessment of Functioning Scale, BPRS Brief Psychiatric Rating Scale a Mann Whitney U test b Fisher s exact test 5 (10.6) 10 (22.2) 34 (72.4) 25 (55.6) 8 (17.0) 10 (22.2) 0.22 b Mean 6.7 3.8 SD 6.0 5.5 Median 6 1 0.008 HAM-D Mean 6.4 2.7 SD 6.4 4.3 Median 6 0 0.005 GAF Mean 75.0 86.1 SD 6.5 7.3 Median 75 90 0.001 BPRS Mean 27.5 25.6 SD 3.3 2.8 Median 27 24 <0.001 substantially confirmed when scores were dichotomized (Table 3). In particular, subjects with the presence of symptoms according to HAM-A and HAM-D scores were at least 3 times more likely to present JHS/EDS-HT than subjects without symptoms (OR 3.13, 95 % CI 0.92 10.7; OR 3.68, 95 % CI 1.36 10.0, respectively), subjects with the presence of symptoms according to the GAF scale were 8 times more likely to present JHS/EDS-HT than subjects without symptoms (OR 7.93; 95 % CI 2.13 29.5), and subjects with high BPRS scale were 5 times more likely to present JHS/EDS-HT than subjects with low BPRS (OR 5.22, 95 % CI 2.15 12.7). Joint hypermobility syndrome/ehlers Danlos syndrome hypermobility type patients were associated with a higher probability of receiving and/or having received psychiatric treatment (OR 7.04, 95 % CI 2.36 21.0). Estimated ORs
for psychiatric diagnosis are illustrated in Table 4. Additional evidence of an higher burden of psychiatric disorders among JHS/EDS-HT cases, as compared to normal controls, is provided in Table 5, which shows an association with any Axis-I psychiatric and any Axis-II personality disorder and a significantly higher likelihood of being an JHS/EDS-HT subject (OR 2.96, 95 % CI 1.17 7.52 and OR 5.81, 95 % CI 1.20 28.2, respectively). The sample size of our study did not allow us to examine the association with specific DSM categories, since Table 3 Dichotomized HAM-A, HAM-D, GAF, and BPRS by case control status: ORs and 95 % CI HAM-A HAM-A Hamilton Anxiety Rating Scale, HAM-D Hamilton Depression Rating Scale, GAF Global Assessment of Functioning Scale, BPRS Brief Psychiatric Rating Scale a Presence 13 b Presence 8 c Presence 70 Cases (N = 47) Control (N = 45) d High 25, upper tercile of controls OR (95 % CI) Absence 36 (76.6) 41 (91.1) 1 Referent P value Presence a 11 (23.4) 4 (8.9) 3.13 (0.92 10.7) 0.07 HAM-D Absence 28 (59.6) 38 (84.4) 1 Referent Presence b 19 (40.4) 7 (15.6) 3.68 (1.36 10.0) 0.01 GAF Absence 30 (63.8) 42 (93.3) 1 Referent Presence c 17 (36.2) 3 (6.7) 7.93 (2.13 29.5) 0.002 BPRS Low 14 (29.8) 31 (68.9) 1 Referent High d 33 (70.2) 14 (31.1) 5.22 (2.15 12.7) <0.001 the beta error would be substantial. However, in spite of the low statistical power, we found an association between JHS/EDS-HT and adjustment disorder estimated by the imprecise but significant OR 22.6 (95 % CI 1.3 407.9). We also estimated large, although not significant ORs for major depression OR 11.9 (95 % CI 0.62 231.3), and obsessive compulsive personality disorder (OCPD) OR 12.8 (95 % CI 0.68 238.4). In particular, we registered OCPD in 5 out of 47 JHS/EDS-HT patients with an overall prevalence of 10.6 % compared to an expected rate in the general population of 2.0 % [24] Accordingly, we did not find OCPD in any of the 45 controls. Since females represent more than 80 % of the study base, we reran the models restricting to this subgroup and the results remain almost the same. Discussion In this case control study, we observed a higher prevalence of psychiatric disorders among subjects affected by JHS/EDS-HT (38 % of Axis-I and 21 % of Axis-II Disorders) as compared to controls. The most interesting finding is that JHS/EDS-HT subjects have a 4.3 relative risk of being affected by any psychiatric disorder. In particular, patients with a previous diagnosis of JHS/EDS-HT have a 5.8 relative risk of having a personality disorder. OCDP was observed in 10.6 % of cases, a rate fivefold higher than the general population [24]. Since OCDP appears significantly more common in JHS/EDS-HT patients, we could speculate on their psychopathologic relationship. In particular, in congenitally hypermobile subjects, the need of a hyper-control might be justified by musculoskeletal consequences or associated features, such as joint instability and lack of proprioception [25], which early occur in their life. In addition, perfectionism may result from the frequent Table 4 Associations between EDS-HT and selected Axis-I and Axis-II psychiatric disorders a Haldane correction of 0.5 was used for zero cell count Characteristics SCID-I no. (%) Cases (N = 47) Controls (N = 45) All OR Females OR (95 % CI) a (95 % CI) a Major depression 4 (100) 0 11.9 (0.62 231.3) 9.73 (0.50 190.3) Dysthymia 2 (66.7) 1 (33.3) 2.67 (0.23 31.0) 2.17 (0.18 25.5) Minor depression 3 (60.0) 2 (40.0) 2.00 (0.31 12.8) 3.25 (0.32 33.4) Adjustment disorder 8 (100) 0 22.6 (1.25 407.9) 14.1 (0.75 262.9) Bulimia 1 (50.0) 1 (50.0) 1.33 (0.08 22.3) 1.08 (0.06 18.3) Panic disorder 2 (50.0) 2 (50.0) 1.33 (0.18 10.1) 0.54 (0.05 6.36) Anxiety disorder NOS 0 3 (100) 0.19 (0.01 3.82) 0.15 (0.01 3.15) SCID-II no. (%) Narcissistic 1 (100) 0 3.48 (0.14 88.0) 3.10 (0.12 78.9) OCDP 5 (100) 0 12.8 (0.68 238.4) 11.3 (0.60 213.9) Histrionic 2 (50.0) 2 (50.0) 1.16 (0.16 8.66) 1.03 (0.14 7.79) Schizoid 2 (100) 0 5.80 (0.27 124.6) 5.16 (0.24 111.8)
Table 5 Associations between EDS-HT and any Axis-I and Axis-II psychiatric disorders a Fisher s exact test Characteristics SCID-I no. (%) Cases (N = 47) Controls (N = 45) P value a All OR (95 % CI) Females OR (95 % CI) Negative 27 (42.9) 36 (57.1) 1 Referent 1 Referent Positive 20 (69.0) 9 (31.0) 0.03 2.96 (1.17 7.52) 2.30 (0.84 6.30) SCID-II no. (%) Negative 37 (46.2) 43 (56.8) 1 Referent 1 Referent Positive 10 (83.3) 2 (16.7) 0.03 5.81 (1.20 28.2) 5.16 (1.05 25.5) SCID combined no. (%) Negative 21 (37.5) 35 (62.5) 1 Referent 1 Referent Positive (I and/or II) 26 (72.2) 10 (27.8) 0.001 4.33 (1.75 10.7) 3.55 (1.33 9.46) lack of recognition and poor knowledge of the syndrome by professionals. As suggested by Millon, OCDP is related to having overly controlling parents [26]; thus, in patients affected by JHS/EDS-HT, this kind of hyper-control may involve both parents and patients. Nevertheless, further explanations in order to interpret this association would be too speculative. The higher frequency of adjustment disorder is not surprising given the chronic and disabling nature of JHS/EDS- HT, as well as the 19 % occurrence of depressive disorders (major depression, minor depression, and dysthymia). Remarkably, we did not observe a higher rate of anxiety disorders, although JHS/EDS-HT still showed higher mean score at HAM-A compared to controls. This finding does not support the findings by Bulbena and co-authors who observed a high rate of panic and other anxiety disorders among JHS patients [17]. Even though panic disorder is a complex condition not simplistically related only to somatic anxiety, the role of cardiovascular dysautonomia might be a confounding factor in JHS/EDS-HT, as previously discussed by other authors [27, 28]. In particular, this feature, usually in the form of postural tachycardia syndrome in JHS/EDS-HT, often presents with dizziness and light-headedness, palpitations, visual disturbances, clamminess, loss of consciousness, nausea, headache, pain (chest or upper abdomen), shortness of breath, and nonspecific symptoms, including fatigue, lethargy, and difficulty thinking or concentrating [29]. When cardiovascular dysautonomia can occur with JHS/EDS-HT, a diagnosis of anxiety disorder according to the DSM-IV criteria could be awkward. An elevated psychological burden in these patients is confirmed by the higher HAM-A, HAM-D, and BPRS scores and by a higher probability of receiving and/or having received psychiatric treatment OR 7.04 (2.36 21.0) as compared to controls. This case control study design allowed us to identify significant associations between the preexistent diagnosis of JHS/EDS-HT and specific psychiatric comorbidities. We acknowledge, however, that the relatively small sample size of the study and its low statistical indicate two use caution in generalizing the results. In particular, no firm inference is at moment possible regarding the association between JHS/EDS-HT and selected DSM categories, and further studies are needed to replicate or refine our results. Another limitation is that we cannot rule out a Berkson s bias. In other words, it is possible that, at least for some patients, the observed association is biased by the higher probability of hospital admittance for subjects with a co-diagnosis of JHS/EDS-HT and psychiatric disorder as compared to those with isolated JHS/EDS-HT. Nevertheless, as in this study, psychiatric disorders were assessed during and not before hospitalization, the chance of a Berkson s bias appears reduced. In spite of the abovementioned study limitations, we were able to identify associations, some of the rather strong, between JHS/EDS- HT and psychiatric disorders. The observed associations are clinically relevant and have health care implications. Doctors dealing with JHS/EDS-HT should be made fully aware of the burden of psychiatric disorders present among these patients. In conclusion, this case control study showed a higher rate of mood and personality disorders in JHS/EDS-HT compared to matched controls. Among them, the association with OCPD may be of major interest and needs further research. However, our findings highlight the utility of a psychiatric assessment for all JHS/EDS-HT patients in order to better support them in coping with their still poorly investigated disabilities. Conflict of interest None. References 1. Grahame R (2010) What is the joint hypermobility syndrome? JHS from the cradle to the grave. In: Hakim AJ, Keer R, Grahame R (eds) Hypermobility, fibromyalgia and chronic pain. Churchill Livingstone Elsevier, Edinburgh, pp 19 34 2. Tinkle BT, Bird HA, Grahame R, Lavallee M, Levy HP, Sillence D (2009) The lack of clinical distinction between the
hypermobility type of Ehlers Danlos syndrome and the joint hypermobility syndrome (a.k.a. hypermobility syndrome). Am J Med Genet A 149A:2368 2370 3. Hakim AJ, Sahota A (2006) Joint hypermobility and skin elasticity: the hereditary disorders of connective tissue. Clin Dermatol 24:521 533 4. Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ (1998) Ehlers Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers Danlos national foundation (USA) and Ehlers Danlos support group (UK). Am J Med Genet 77(1):31 37 5. Grahame R, Bird HA, Child A (2000) The revised (Brighton 1998) criteria for the diagnosis of benign joint hypermobility syndrome (BJHS). J Rheumatol 27:1777 1779 6. Mayer K, Kennerknecht I, Steinmann B (2013) Clinical utility gene card for Ehlers Danlos syndrome types I VII and variantsupdate 2012. Eur J Hum Genet 21(1). doi:10.1038/ejhg.2012.162 7. Hakim AJ, Grahame R (2003) Joint hypermobility. Best Pract Res Clin Rheumatol 17:989 1004 8. Castori M, Sperduti I, Celletti C, Camerota F, Grammatico P (2011) Symptom and joint mobility progression in the joint hypermobility syndrome (Ehlers Danlos syndrome, hypermobility type). Clin Exp Rheumatol 29:998 1005 9. Castori M, Morlino S, Celletti C, Ghibellini G, Bruschini M, Grammatico P, Blundo C, Camerota F (2013) Re-writing the natural history of pain and related symptoms in the joint hypermobility syndrome/ehlers Danlos syndrome, hypermobility type. Am J Med Genet A (in press) 10. Lumley MA, Jordan M, Rubenstein R, Tsipouras P, Evans MI (1994) Psychosocial functioning in the Ehlers Danlos syndrome. Am J Med Genet 53:149 152 11. Ercolani M, Galvani M, Franchini C, Baracchini F, Chattat R (2008) Benign joint hypermobility syndrome: psychological features and psychopathological symptoms in a sample pain-free at evaluation 1. Percept Mot Skills 107:246 256 12. Baeza-Velasco C, Gely-Nargeot MC, Vilarrasa AB, Fenetrier C, Bravo JF (2011) Association between psychopathological factors and joint hypermobility syndrome in a group of undergraduates from a French university. Int J Psychiatry Med 41:187 201 13. Garcìa Campavo J, Asso E, Alda M, Andres EM, Sobradiel N (2010) Association between joint hypermobility syndrome and panic disorder: a case control study. Psychosomatics 51:55 61 14. Garcia-Campavo J, Asso E, Alda M (2011) Joint Hypermobility and anxiety: the state of the art. Curr Psychiatry Rep 13:18 25 15. Martin-Santos R, Bulbena A, Crippa JA (2010) Anxiety disorders, their relationship to hypermobility and their management. In: Hakim AJ, Keer R, Grahame R (eds) Hypermobility, fibromyalgia and chronic pain. Churchill Livingstone Elsevier, Edinburgh, pp 56 60 16. Martín-Santos R, Bulbena A, Porta M, Gago J, Molina L, Duró JC (1998) Association between joint hypermobility syndrome and panic disorder. Am J Psychiatry 155(11):1578 1583 17. Bulbena A, Gago J, Pailhez G, Sperry L, Fullana MA, Vilarroya O (2011) Joint hypermobility syndrome is a risk factor trait for anxiety disorders: a 15-year follow-up cohort study. Gen Hosp Psychiatry 33(4):363 370 18. First MB, Spitzer RL, Gibbon M, Williams JB (2000) Structured clinical interview for DSM-IV Axis I disorders, clinical version (SCID-I CV). Florence, Italy: Organizzazioni Speciali. (Italian version by Mazzi F, Morosini P, de Girolamo G, et al.) 19. First MB, Gibbon M, Spitzer RL, Williams JBW, Benjamin LS (1997) Structured clinical interview for DSM-IV Axis II personality disorders, (SCID-II). American Psychiatric Press Inc., Washington, DC 20. Hamilton M (1959) The assessment of anxiety states by rating. Br J Med Psychol 32:50 55 21. Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56 62 22. Overall JE, Gorham DR (1962) The brief psychiatric rating scale. Psychol Rep 10:799 812 23. Stata Corp. (2009) Stata statistical software: release 11. Stata Corp LP, College Station, TX 24. Torgersen S, Kringlen E, Cramer V (2001) The prevalence of personality disorders in community sample. Arch Gen Psychiatry 58:590 596 25. Celletti C, Camerota F (2013) The multifaced and complex hypermobility syndrome (a.k.a. Ehlers Danlos syndrome hypermobility type: evaluation and management through a rehabilitative approach. La Clin Terapeutica 164:e325 e335 26. Millon T (1981) Disorders of personality: DSM-III, Axis II. Wiley, New York 27. Bulbena A, Pailhez G, Gago J (2004) Connective tissue between panic disorder and dysautonomia. Am J Med 116(11):783 author reply 783 4 28. Gazit Y, Nahir AM, Grahame R, Jacob G (2003) Dysautonomia in the hypermobility syndrome. Am J Med 115:33 40 29. Mathias CJ, Low DA, Iodice V, Owens AP et al (2012) Postural tachycardia syndrome-current experience and concepts. Nat Rev Neurol 8:22 34